Antispasmodic agents



Patented Dec. 11, 1945 PATENT orirlcs ANTISPASMODIO AGENTS Andrew G.Richardson, Richmond, Va., assignor to William P. Poythross & Company,Inc., Richmond, Va... a corporation of Virginia No Drawing. ApplicationAugust 3, 1943, Serial No. 497,263

4 Claims. (Cl. zoo-239) This invention relates to new compounds havinguseful antispasmodic properties. The invention embraces di-N-substitutedaminoethyl esters of diphenylthioacetic acid of the formula in which Itrepresents a disubstituted amino radi;

cal of the group consisting of the diethylamino group CHz CHI Thecreation of spasmolytic or antispasmodic drugs by organic synthesis hasbeen the subject of much research in the past 'decade. The purpose of aspasmolytic drug is to relieve spasms of smooth muscles. Smooth musclesline most of the visceral organs. The peristalsis and muscular activityof the stomach, intestines, gall bladder, urinary bladder, the uterus,and to a degree the heart are all largely controlled b'y.smooth muscles.Smooth muscles are innervated by the autonomic nervous system.- Theautonomic nervous system consists of two antagonistic branches-thesympathetic branch, and the 40 parasympathetic branch. ,On all visceralorgans except the heart'the parasympathetic nerve impulses increase theirritability and tension of the smooth muscles; contrariwise, thesympathetic nerve impulses increase the tension and irritability of themuscles of the heart muscle and relax the parasympathetic branch of theautonomic nervous system may often be corrected by administeringatropine (an active-alkaloid of belladonna) which serves to break aconnection between the parasympathetic nerve and the smooth muscle. Thisability and effect of atropine is called a neurotropic efiect. A spasmintrinsic in the smooth muscle itself may often be corrected bypapaverine (a derivative of opium which is classed as a narcotic).Papaverine has an ability to decrease intrinsically the contractility ofsmooth muscle; it has the ability to relax smooth muscles directly. Thisability and effect of papaverine is called a ,mu'sculotropic effect.

In relieving spasms of smooth muscles generally, a musculotropic efiectis acknowledged to be superior to a neurotropic effect. A neurotropiceffect cannot relieve spasms intrinsic in the smooth muscle itself,while a musculotropic effect, by relaxing and decreasing theirritability and responsiveness of smooth muscle to stimulation from theautonomic nervous system, can help to relieve a smooth muscle spasm evenwhen it is dueto exaggerated impulses from tne autonomic nervous system.

A clinical difliculty with atropine is that of undesirableside-reactions. Atropine, when given in effective doses, serves to breakor partly break all the parasympathetic nerve-smooth muscle connectionsall over the body. Thus when atropine is given in suflicient dosage torelieve a spasm in a specific visceral organ, such as a gastric orintestinal spasm- (the spasm caused by exaggerated nerve impulses fromthe parasympathetic nervous system) undesirable sideactions due to thebreaking of the parasympathetic nerve-muscle connections elsewhere inthe body may occur. The most easily recognized of these undesirable sidereactions are dilation of the pupil and dryness of the mouth; caused bythe breaking of the parasympathetic connections to the oculomotormuscles and the saliva producing mechanism respectively.

Atropine'is acknowledged to have also a musculotropic effect, but itsneurotropic efiect is so saturated with hydrogen sulfide.

tropic effect. If successful, such substitution would permit the givingof the synthesized compound in much greater dosage before encounteringthe undesirable side reactions due to excessive neurotropic effect. Thegreater dosage would, of course, multiply the musculotropic effectpreserved from the atropine molecule until it reached an intensitysufficient for therapeutic usefulness.

My invention is based upon my discovery that the thio analogs of certaindisubstituted acetic acid esters of amino alcohols have desirableantispasmodic properties.- I have prepared the following closely relatedspecific compounds'of this group andhave found each of them to be usefulas antispasmodics and superior to the corresponding compounds in whichthe acid group of the diphenyl acetic acid is a simple carboxyl groupinstead of the thio carboxylic acid group.

B-diethylaminoethyl diphenylthioacetate CH-COS-CHrCHrv CHz-CH:

B-piperidinoethyl diphenylthioacetate CHrCHz B-morpholinoethyldiphenylthioacetate The procedure followed to carry out the abovereactions is as follows:

22.4 gm. of potassium hydroxide were dissolved in 400 cc. of ethanolcontained in a 1-liter flask equipped with a mechanical stirrer. Theflask was immersed in an ice-salt bath and the solution 46.1 gm. ofdiphenylacetyl chloride previously dissolved in benzene was then addedslowly to the potassium hydrosulfide solution while stirring. Stirringwas continued for thirty minutes. was filtered with suction and thefiltrate evaporated slowly under reduced pressure. The residue was thendissolved in distilled water and dilute hydrochloric acid added slowlyuntil precipitation was complete. precipitate was collected on a filter,dissolved in dilute alkali and reprecipitatedwith dilute hydrochloricacid: The purified solid was filtered with suction, washed thoroughlywith distilled water and dried by means of a vacuum pump and then byletting it stand in a desiccator over sodium Then the mixture Theyellowish-white ture on a water bath, not over 40 C. The mixture wasthen filtered and the filtrate evaporated under reduced pressure. Theresidue, B-chloroethyl diphenylthioacetate, was recrystallized from amixture of diethyl ether and petroleum ether. Melting point: 4547 C.

A mixture of 20 gm. of B-chloroethyl diphenylthioacetate and 20 gm.(excess) of diethylamine were heated in a sealed bottle for three daysat 40 C. in a constant temperature oven. After cooling the reactionmixture was suspended in water and extracted by shaking with diethylether. The ether extract was dried over calcium chloride and the solventevaporated. The B- diethylaminoethyl diphenylthioacetate thus obtainedwas dissolved in anhydrous ether and hydrogen chloride passed into thesolution. Whereupon the ester hydrochloride precipitated. This wascollected by filtration, and recrystallized from a mixture of alcoholand ether. Melting point: 82-85 C.

The hydrochloride is preferred for use as a drug because of its greaterwater solubility than the basic ester.

Example 2.A mixture of 0.1 mole of B-chloroethyl diphenylthioacetateprepared as described in Example 1, and 0.3 mole of morpholine wereheated in a sealed bottle for three days at 40 C. in a constanttemperature oven. After cooling the reaction mixture was suspended inwater and'extracted with ether. The ether extract was then evaporatedand the residue purified by recrystallization from ethanol. The basicester, B-morpholinoethyl diphenylthioacetate, thus obtained was dried,dissolved in anhydrous ether and treated with dry hydrogen chloridewhereupon the ester hydrochloride precipitated. This was collected andrecrystallized from a mixture of ethanol and ether. Melting point of thehydrochloride: 194-196 C.

Example 3.-B-piperidinoethyl diphenylthioacetate hydrochloride wasprepared in exactly the same Way as the morpholino derivative from 0.1mole of B-chloroethyl diphenylthioacetate and 0.3 mole of piperidine.Melting point of the hydrochloride: 210-212 C.

It will be noted that the procedure described "above in Examples 2 and 3for the preparation of the morpholino and the piperidino-compoundsdifiers from the method for the preparation of the diethylamino compounddescribed in Example 1 with respect to therecovery of the compounds fromthe reaction mixtures in which the B-chloroethyl diphenylthioacetate iscombined with the morpholine, piperidine and diethylamine. Thisdifference in the procedures is due to the fact that the morpholino andpiperidino basic esters are crystalline solids whereas the diethylaminobasic ester is a liquid andrequires a different treatment for itsrecovery and purification.

Comparativepharmacological tests on the excised rat uterus, the excisedrabbit intestine, and the excised human uterus have demonstrated thatthe B-diethylaminoethyl diphenylthioacetate administered as thehydrochloride has a musculotropic action about twice that of thecorresponding non-thio or simple acetate compound, that is, the sameantispasmodic effect is obtained by the use of a, concentration of thethioacetate compound equal to half of the concentration of the simpleacetate compound required to give the specified antispasmodic eiiect.

The thioacetate compound presumably has some neurotropic action but itis so weak or small as to be of little or no consequence in the use ofthe drug and has not been accurately measured.

Tests made to determine the toxicity of the thioacetate compoundindicate that its toxicity is very low and practically negligible. Intests made on white rats both young and mature, the

'minimum lethal doses of the thio and non-thio compounds areapproximately the same. The minimum lethal dose was found to varyconsiderably with the age of the rats, being 1.5 grams per kilogram ofbody weight for rats 4 months old and only about 0.5 gram per kilogrambody weight for rats 45 days old. This low toxicity of the thio compoundwas contrary to logical expectation.

The antispasmodic action of the morpholino and piperidino thioacetatecompounds .of Examples 2 and 3 was found to be approximately equal tothat of the B-diethylaminoethyl diphenylthioacetate compound of Example1 and their neurotropic action and toxicity well within the permissiblerange of-tolerance for the use of the compounds as antispasmodic drugs.

The thio compounds have been found to have a distinct advantage over thenon-thio compounds with respect to stability. This result, like thediscovery of the low toxicity of the thio compounds, was contrary tological expectation.

This greater stability of the thio compounds appears as a factor intheir preparation and use. For instance, in the preparation ofB-diethylaminoethyl diphenylacetate it was found thatthe hydrochloridesalt could not be mad in the usual way by dissolving the basic ester inether and passing hydrogen chloride into the solution because hydrolysisof the ester occurs under these conditions. This customary proceduremay, ,however, be applied for the production of the corresponding thiocompound without hydrolysis. Moreover, when it was attempted to purifythe non-thio compound by recrystallization from alcohol hydrolysisoccurred whereas th thio compound was stable under these conditions. The

thio compound was found to be stable in aqueous solution for a period ofat least two weeks. i

So far as I am aware, the thre compounds described in Examples 1, 2 and3 are new and no one heretofore has suggested their use a drugs.

I claim:

1. A di-N-substituted aminoethyl ester of diphenylthioacetic acid of theformula CH-COS-CHr-CHzR in which R represents a disubstituted aminoradical of the group consisting of the diethylamino group, themorpholino group and the piperidino group.

2. A compound of the formula on-cos-omcm-rr 3. A compound of the formulaCH-00S-CH:CH|N\ on, O CHr-Ca 4. A compound of the formulaore-cos-cr-ncrn-- o O CHr-Ca ANDREW c. RICHARDSON.

